REFERENCES

INTRODUCTION

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Transplantation is the act of transferring cells, tissues, or organs from one site to another. The malfunction of an organ system can be corrected with transplantation of an organ (e.g., heart, lung, kidney, liver, or pancreas) from a donor. However, the immune system remains the most formidable barrier to transplantation as a routine medical treatment. The immune system has developed elaborate and effective mechanisms to combat foreign proteins. These mechanisms are also involved in the rejection of transplanted organs, which are recognized as foreign by the recipient's immune system.

HISTORY

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In 1944, Medawar showed that skin allograft rejection is a host versus graft response. Mitchison later demonstrated the cell-mediated features of this response. The first successful identical twin transplant of a human kidney was performed by Joseph E. Murray in 1954 in Boston, followed by the first successful liver transplant by Thomas E. Starzl in 1967, the first heart transplantation by Christian Barnard in 1967, and the first successful bone marrow transplant by E. Donnall Thomas in 1968. Schwartz and Dameshek, in 1959, showed that 6-mercaptopurine was immunosuppressive in rats, ushering in the era of immunosuppressive drug treatment. Since then, many new and progressively more selective immunosuppressive agents have been developed. These therapies have enabled the transplantation of and improved the survival of transplanted organs.

TYPES OF GRAFTS

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The degree of immune response to a graft depends partly on the degree of genetic disparity between the grafted organ and the host. Xenografts, which are grafts between members of different species, have the most disparity and elicit the maximal immune response, undergoing rapid rejection. Autografts, which are grafts from one part of the body to another (e.g., skin grafts), are not foreign tissue and, therefore, do not elicit rejection. Isografts, which are grafts between genetically identical individuals (e.g., monozygotic twins), also undergo no rejection.

Allografts are grafts between members of the same species that differ genetically. This is the most common form of transplantation.

The degree to which allografts undergo rejection depends partly on the degree of similarity or histocompatibility between the donor and the recipient.

The degree and type of response also vary with the type of the transplant. Some sites, such as the eye and the brain, are immunologically privileged (i.e., they have minimal or no immune system cells and can tolerate even mismatched grafts). Skin grafts are not initially vascularized and so do not manifest rejection until the blood supply develops. The heart, kidneys, and liver are highly vascular organs and lead to a vigorous cell mediated response in the host.

IMMUNOBIOLOGY OF REJECTION

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The basis for alloreactive response is genetic incompatibility of components of tissue that are antigenic between the donor and the recipient. These molecules can be classified into three broad categories: (a) major histocompatibility antigens (MHC antigens); (b) minor histocompatibility antigens (mHags); and (c) tissue specific antigens (non MHC).

MAJOR HISTOCOMPATIBILITY ANTIGENS

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The strongest antigens expressed by tissues are major histocompatibility antigens (MHC antigens). The MHC molecules act as primary antigens responsible for the induction of the immune response against a transplanted organ. The MHC (or “human leukocyte antigen or HLA system) of man is located on the short arm of chromosome 6. Each individual expresses the MHC genes genes from both the alleles on the cell surface. They are inherited as 2 half sets (one from each parent). This makes a person half identical to each of his or her parents with respect to the MHC complex. This also leads to a 25% chance that an individual might have a sibling who is HLA identical.

The MHC molecules are divided into 2 classes. The HLA class I molecules (i.e. HLA-A, -B, and –C) are normally expressed on all nucleated cells, whereas the class II molecules (i.e. HLA-DP, -DQ, and –DR) are expressed only on the professional antigen-presenting cells (APCs), such as dendritic cells, activated macrophages, and B cells. The physiological function of the MHC molecules is to present antigenic peptides to T cells, since the T lymphocytes only recognize antigen when presented in a complex with an MHC molecule. The HLA class I molecules are responsible for presenting antigenic peptides from within the cell (e.g. antigens from the intracellular viruses, tumor antigens, self-antigens) to CD8 T cells. The HLA class II molecules present extracellular antigens such as extracellular bacteria to CD4 T cells.

MINOR HISTOCOMPATIBILITY ANTIGENS

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Minor histocompatibility antigens (or mHags) are receptors on the cell surface of donated organs that are known to give an immunological response in some organ transplants. They cause problems of rejection less frequently than those of the major histocompatibility complex. Even if it were possible to match donor and recipient at every locus of the MHC, some tissue incompatibility would still remain (except between identical twins). So far more than 19 autosomal and Y-chromosome-encoded minor histocompatibility antigens have been identified in humans. These include: (a) H-Y, an antigen encoded on the Y chromosome and thus present in male, but not female, tissue, and (b) HA-2, an antigen derived from the contractile protein myosin.

Minor histocompatibility antigens cause only weaker reactions, but combinations of several minor antigens can elicit strong rejection responses. For example, a woman with aplastic anemia rejected the bone marrow transplanted from her HLA-identical brother. Cytotoxic T cells isolated from the patient’s blood lysed the cells that were HLA matched and of male origin. The T cell reactivity observed in this case was restricted to male cells, thus indicating that the target structures (i.e., minor histocompatibility antigens) had to be encoded by H-Y gene on the Y chromosome. The mHags are presented as peptides on the cell surface primarily by MHC class I molecules.

TISSUE SPECIFIC ANTIGENS

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A third group of antigens expressed on transplanted organs are specific to a particular organ or tissue (i.e., tissue specific antigens). The expression of these antigens is restricted to various tissues and organs. There are a myriad of tissue specific antigens that have been characterized. But no comprehensive study of these antigens is available because of technical limitations. Most of the knowledge on this class of antigens has come from immunohistochemical analyses of rejected grafts from MHC-matched organs. It is recognized that they exhibit some degree of polymorphism among individuals due to variation in their primary or secondary structures. These differences are the causative agents of alloreactivity.

Transplant rejection is a process in which the recipient’s immune system recognizes the graft as being foreign and attacks it. The antigens responsible for such rejection are primarily major histocompatibility antigens with a smaller contribution of mHags and tissue specific antigens. The immune response to a transplanted organ consists of both cellular (lymphocyte mediated) and humoral (antibody mediated) mechanisms. Although other cell types are also involved, the T cells are central in the rejection of grafts. The relative contributions of these two mechanisms to rejection vary among grafts and are reflected in the histologic features of the rejected organs.

T-CELL MEDIATED REACTIONS

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T-cell mediated reaction is called cellular rejection and is induced by two mechanisms: (a) destruction of graft cells by CD8+ cytotoxic lymphocytes and (b) delayed hypersensitivity reactions triggered by activated CD4+ helper cells. The recipient T cells recognize antigens in the graft (alloantigens) by two pathways, called direct and indirect.

1. Direct pathway

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In the direct pathway T cells of the transplant recipient recognize donor MHC molecules on the surface of APCs in the graft. It is believed that dendritic cells carried in the donor organs are the most important APCs for initiating the antigraft response, because they not only express high levels of class I and II MHC molecules but also are endowed with costimulatory molecules. The T cells of the host encounter the donor dendritic cells within the grafted organ. Both the CD4+ and the CD8+ T cells are involved in this reaction. CD8+ T cells recognize class I MHC molecules and differentiate into active cytotoxic T cells. Once mature cytotoxic T cells are generated they kill the grafted tissue. CD4+ helper T cells recognize allogeneic class II molecules and proliferate and differentiate into TH1 effector cells. Cytokines secreted by the activated CD4+ T cells trigger a delayed hypersensitivity reaction in the graft, resulting in increased vascular permeability and local accumulation of lymphocytes and macrophages, and graft injury caused by the activated macrophages.

2. Indirect pathway

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In the indirect pathway, recipient T lymphocytes recognize MHC antigens of the graft after they are presented by the recipient's own APCs. The MCH molecules from the donor tissue are presented by the host's own antigen presenting cells, like any other foreign peptide. Thus, the indirect pathway is similar to the physiologic processing and presentation of other foreign (e.g., microbial) antigens.

The indirect pathway generates CD4+ T cells that enter the graft and recognize graft antigens being displayed by host APCs that have also entered the graft, and the result is a delayed hypersensitivity type of reaction. However, CD8+ CTLs that may be generated by the indirect pathway cannot directly recognize or kill graft cells, because these CTLs recognize graft antigens presented by the host's APCs. Therefore, when T cells react to a graft by the indirect pathway, the principal mechanism of cellular rejection may be T-cell cytokine production and delayed hypersensitivity. It is postulated that the direct pathway is the major pathway in acute cellular rejection, whereas the indirect pathway is more important in chronic rejection.

ANTIBODY-MEDIATED REACTIONS

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Although T cells are pivotal in the rejection of organ transplants, antibodies produced against alloantigens in the graft are also important mediators of rejection. This process is called humoral rejection, and it can take two forms.

1. Recipients are previously sensitized to transplantation antigens

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When preformed antidonor antibodies are present in the circulation of the recipient before transplantation, hyperacute rejection occurs. Such antibodies may be present in a recipient who has previously rejected a kidney transplant. Multiparous women who develop anti-HLA antibodies against paternal antigens shed from the fetus may have preformed antibodies to grafts taken from their husbands or children, or even from unrelated individuals who share HLA alleles with the husbands. Prior blood transfusions can also lead to presensitization, because platelets and white blood cells are rich in HLA antigens and donors and recipients are usually not HLA-identical.

When preformed antidonor antibodies are present, rejection occurs immediately after transplantation because the circulating antibodies react with and deposit rapidly on the vascular endothelium of the grafted organ. Complement fixation occurs, resulting in endothelial cell death, thrombosis of vessels in the graft and ischemic death of the graft. With the current practice of cross-matching, that is, testing recipient's serum for antibodies against donor's cells, hyperacute rejection is no longer a significant clinical problem.

2. Recipients are not previously sensitized to transplantation antigens

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In recipients not previously sensitized to transplantation antigens, exposure to the class I and class II HLA antigens of the donor graft may evoke antibodies. The antibodies formed by the recipient may cause injury by several mechanisms, including complement-dependent cytotoxicity, inflammation, and antibody-dependent cell-mediated cytotoxicity. The initial target of these antibodies in rejection seems to be the graft vasculature. Thus, antibody-dependent acute humoral rejection is usually manifested by a vasculitis, sometimes referred to as rejection vasculitis. The mechanism of vasculitis consists in recipients CD4+ T lymphocytes recognizing foreign HLA class II antigens in the allograft. They stimulate B lymphocytes to produce high affinity and high titer antibodies against the allograft.

The major histocompatibility, minor histocompatibility and tissue specific antigen differences between the donor and recipient results in rejection reactions and are manifested clinically as host-versus-graft or as graft-versus host responses. In extreme cases these responses result in the loss of the graft or in the graft-versus-host responses that can culminate in the death of the patient. However in the absence of an immune response or subsequent to overcoming one, the patient may achieve graft acceptance and true immunologic tolerance.2010-07-19 18:44Читать похожую статью